Misuse of pharmaceutical opioid analgesics presents an increasingly severe public health problem (Paulozzi et al., 2006) as rates of overdose and death from non-medical use continue to rise (Hall et al., 2008; SAMHSA, 2004). The Food and Drug Administration now requires Risk Evaluation and Mitigation Strategies (REMS) to ensure the benefits of these analgesics outweigh the risks associated with them (FDA, 2008). The increasing prevalence of pharmaceutical opioid misuse, unabated by current regulations and policies, suggests that a comprehensive system-level framework is necessary to develop more effective interventions. A system dynamics approach captures the complex dynamics of pharmaceutical opioid use and may provide insight into the development of interventions and policies that limit misuse of these products. The proposed research integrates data on the prescription, diversion, and misuse of opioid analgesics into a system-level database that provides a foundation for a system dynamics model. This model tests the impacts of several proposed interventions on opioid diversion and misuse, including tamper resistant drug formulations and prescription monitoring programs. Expected results include estimates for the percentage change in opioid-related deaths. Two specific aims are proposed: Specific Aim 1: Build a system-level database, estimate model parameters, and measure the model's ability to explain variation over time in 1) the prevalence of misuse, abuse, and dependence on pharmaceutical opioid pain medications by medical users, 2) initiation and prevalence of non-medical users, and 3) prevalence of opioid overdose deaths. Hypothesis 1: The system-level dynamic model explains a significant proportion of the variation over time in misuser populations and deaths related to pharmaceutical opioids. Specific Aim 2: Simplify and Refine model logic and data, and evaluate potential REMS interventions and the likelihood of adverse distal outcomes. Hypothesis 2a: Tamper resistant formulations reduce diversion and misuse of Schedule II opioid medications and related opioid deaths but lead to increased diversion, misuse, and deaths related to Schedule II and III opioids without tamper resistance. Hypothesis 2b: Expansion of prescription monitoring programs decreases doctor shopping and prescription forgery without adverse long-term effects. Relevance Effective policies and regulations are needed to prevent, detect, and treat misuse of opioid medications. Due to the complex interactions between medical use, misuse, and the diversion of drugs to non-medical users, a system-level model is proposed to assess the impacts of interventions such as tamper resistant drug formulations and prescription monitoring systems on adverse public health outcomes such as opioid-related deaths.